Abstract. CD154 (CD40L) is a key target for immunomodulation due to its central role in controlling the activation of the immune system. This well studied immune ?switch? has been the focus of extensive drug development for over two decades. The validation of this drug target consists of reproducible and robust data using rodent and NHP models of chronic inflammation, autoimmune disease and organ transplant. In fact, this is one of the few undeveloped drug targets where antibodies have shown promising therapeutic efficacy in treating human autoimmune disease in several clinical trials. Therefore, the choice of CD154 as a drug target for commercial development is clear. The limitation on commercializing this clinical success was based on the thromboembolic toxicity of the drugs used in early trials and the limited knowledge on the cause of these adverse events (AEs). Consequent to these early trials the mechanism of toxicity was shown to be related to the FcR binding capacity of those former antibody drugs. Aggressive approaches to fix the AE's have proven successful in early human trials however these molecules show reduced potency in inhibiting the CD154 pathway likely owing to the use of non-conventional drug design. ImmuNext's engineering and development of a high affinity anti-CD154 antibody (INX021) shows that silencing the platelet Fc binding and ablating the complement fixation properties of the molecule eliminates the risk of thromoboembolic toxicity as demonstrated in vitro and an in vivo non-GLP NHP tox study. INX021 is a high affinity drug with a long half-life and likely low immunogenicity. Together, these features place INX021 as a best-in-class drug for several disease indications. Systemic lupus erythematosus is the first indication of choice. The mechanisms of action of CD154 also suggest that treating idiopathic thrombocytopena, IBD and TNF-resistant RA are plausible alternative indications to be considered following the completion of human safety studies. The Specific Aims of this proposal are: 1. Process Development, Formulation Development & Manufacture of GLP Tox Material. 2. Design of Phase 1A and 1B Clinical Trials and Supporting GLP Tox Study When these Aims are complete, ImmuNext can perform the IND-enabling GLP tox study that will enable partnering of this asset. Induction of tolerance - the `holy grail' of immunology - will be one step closer to commercial reality.